Catalytic asymmetric hydrogenation

ABSTRACT

1. A PROCESS FOR THE ASYMMETRIC HYDROGENATION OF AN OLEFIN WHICH COMPRISES THE HYDROGENATION OF AN OLEFIN OF THE FORMULA   R1-C(-R2)=C(-R3)-R4   WHEREIN R1, R2, R3 AND R4 ARE EACH INDEPENDENTLY SELECTED FROM THE GROUP CONSISTING OF HYDROGEN; ALKYL HAVING AT LEAST ONE AND A MACIMUM OF 12 CARBON ATOMS; SUBSTITUTED ALKYL SAID SUBSTITUTION BEING SELECTED FROM THE GROUP CONSISTING OF AMINO, HYDROXY, NITRO, THIO, CARBONYL, CARBOXYL, CARBOXYLIC ESTER, SAID ESTER GROUP HAVING A MAXIMUM OF 6 CARBON ATOMS; PHENYL; SUBSTITUTED PHENYL, SAID SUBSTITUTION BEING SELECTED FROM THE GROUP CONSISTING OF ALKYL HAVING A MAXIMUM OF 4 CARBON ATOMS, AMINO, CARBOXYL, NITRO AND CARBOXYLIC ESTER, SAID ESTER HAVING A MAXIMUM OF 4 CARBON ATOMS, AND SAID SUBSTITUTION BEING LESS THAN 3 SUBSTITUTENTS; AMINO; DIBENZYLAMINO; BENZYLAMINO; NITRO; CARBOXYL AND CARBOXYLIC ESTER, SAID ESTER HAVING A MAXIMUM OF 4 CARBON ATOMS, PROVIDED THAT, UPON HYDROGENATION, (A) THE OLEFIN IS CAPABLE OF FORMING A RACEMIC MIXTURE, AND (B) AT LEAST ONE OF THE CARBON ATOMS UNITED BY THE OLEFINIC BOND IS CAPABLE OF FORMING AN ASYMMETRIC CARBON, IN THE PRESENCE OF A CATALYST REPRESENTED BY THE FORMULA   M1XNL3   WHEREIN M1 IS A METAL SELECTED FROM THE GROUP CONSISTING OF RHODIUM, RUTHENIUM AND IRIDIUM; X IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, CHLORINE, FLUORINE, BROMINE AND IODINE; EACH L IS INDEPENDENTLY SELECTED FROM THE GROUP AR5R6R7, WHEREIN A IS SELECTED FROM THE GROUP CONSISTING OF PHOSPHORUS AND ARSENIC AND R5, R6 AND R7 ARE EACH INDEPENDENTLY SELECTED FROM THE GROUP CONSISTING OF HYDROGEN; ALKYL HAVING AT LEAST ONE CARBON ATOM AND A MAXIMUM OF 12 CARBON ATOMS; SUBSTITUTED ALLKYL, SAID SUBSTITUTION SELECTED FROM THE GROUP CONSISTING OF AMINO, CARBONYL, PHENYL, NITRO AND ALKOXY, SAID ALKOXY HAVING A MAXIMUM OF 4 CARBON ATOMS; PHENYL; SUBSTITUTED PHENYL, SAID SUBSTITUTION SELECTED FROM THE GROUP CONSISTING OF ALKYL HAVING A MAXIMUM OF 4 CARBON ATOMS, AMINO AND NITRO, SAID SUBSTITUTION BEING LESS THAN 3 SUBSTITUENTS; CYCLOALKYL HAVING AT LEAST 3 CARBON ATOMS AND A MAXIMUM OF 6 CARBON ATOMS; PYRRYL; THIENYL; FURYL; PYRIDYL AND PIPERIDYL, PROVIDED THAT AT LEAST ONE L GROUP IS OPTICALLY ACTIVE AND N IS ONE OF THE INTEGERS ONE OR THREE.

"United States Patent CATALYTIC ASYMMETRIC HYDROGENATION William S. Knowles and M. Jerome Sabacky, St. Louis,

Mo., assiguors to Monsanto Company, St. Louis, M0. N0 Drawing. Continuation of abandoned application Ser.

No. 758,603, Sept. 9, 1968. This application Aug. 20,

1971, Ser. No. 173,620

Int. Cl. C07b 1/00 U.S. Cl. 260-490 15 Claims ABSTRACT OF THE DISCLOSURE Process for the homogeneous catalytic hydrogenation of olefins, capable of existing as enantiomorphs upon hydrogenation of the olefinic bond, which yields on hydrogenation an optically active mixture. The process com prises the hydrogenation of the olefin in the presence of an optically active coordinated metal hydrogenation catalyst, in which the metal is selected from the group consisting of rhodium, iridium, ruthenium, osmium, palladium and platinum.

This process is a generalized process for any asymmetric hydrogenation of olefins in which one optical enantiomorph is desired. It is also a generalized process for the selective hydrogenation of olefins in the presence of other reactive groups which are easily hydrogenated. It is especially useful for the preparation of natural products which possess optical activity, such as amino acids, and for products such as flavors, fragrances which may require optical activity for their utilization.

This invention also relates to new optically active coordinated hydrogenation catalysts.

:1 This application is a continuation of our co-pending application Ser. No. 758,603, filed Sept. 9, 1968 and now abandoned. 2

When an olefin, which in its saturated form is optically active, is hydrogenated, the usual resultant product is optically inactive mainly because an equal amount of both optical antipodies (racemic mixture) are formed. To obtain'the desired optical antipode, the mixture must be separated into its optical components. This procedure is laborious,-expensive, and often results in destruction of the 3,849,480 Patented Nov. 19, 1974 than 3 substituents, amino, benzylamino, dibenzylamino. nitro, carboxyl and carboxylic ester, said esterhaving a maximum of 4 carbon atoms, provided that at least one of the ethylenic carbons on hydrogenation is asymmetric.

The groups R R R and R may also have an asymmertic carbon. This would not prevent the formation of an additional asymmetric carbon on hydrogenation. The optically active hydrogenation catalyst used in this invention is a coordination complex of a metal selected from the group consisting of rhodium, iridium, ruthenium, osmium, palladium and platinum, with a phosphine or arsine moiety of the formula AR R R wherein A is phosphorus or arsenic and R R and R are each independently selected from the group consisting of hydrogen, alkyl, having at least one carbon atom and a maximum of 12 carbon atoms, substituted alkyl, said substitution selected from the group consisting of amino, carbonyl, phenyl, nitro and alkoxy, said alkoxy having a maximum of 4 carbon atoms, phenyl, substituted phenyl, said sub stitution selected from the group consistingof alkyl having a maximum of 4 carbon atoms, amino and nitro, said substitution being less than 3 substituents, cycloalkyl having at least 3 carbon atoms and a maximum of 6 carbon atoms, pyrryl, thienyl, furyl, pyridyl and piperidyl. At least one of the moieties AR R R must be optically active.

Optical activity of the metal coordinated complex, according to this invention, resides in the phosphine or arsine moiety. This optical activity may result either from having three different groups on the phosphorus or arsenic atom or by having an optically active group attached to the phosphorus or arsenic atom.

The coordination complex is represented by the formula M X,,L or M X L wherein M is a metal selected undesired optical antipode. Due to these difiiculties, in-

creased attention has been placed on asymmetric synthesis in which one of the enantiomorphs is obtained in major amounts.

It has now been found that olefinic bonds can be selectively hydrogenated, in the presence of an optically active optically active the remaining twdg'roups may coordinated metal hydrogenation catalyst, to yield an optically active compound, according to the following equation: I

Bi R H H R l I (1: +112 optically;; active R:/ R ca a ys R wherein R R R and R are each independently selected from the group consisting of hydrogen, alkyl, having at least one and a maximum of 12 carbon atoms, substituted alkyl said substitution being selected from the group consisting of amino, hydroxy, nitro, thio, carbonyl, carboxyl, carboxylic ester, said ester group having a maximum of 6 carbon atoms, phenyl, substituted phenyl, said substitution being selected from the group consisting of alkyl having a maximum of 4 carbon atoms, amino, carboxyl, nitro and carboxylic ester, said ester having a maximum of 4 carbon atoms and said substitution being less from the group consisting of rhodium, iridium, ruthenium and osmium; M is selected from the group consisting of palladium and platinum; X is selected from the-group consisting of hydrogen, fluorine, bromine, chlorine and iodine; L is the ligand (AR R R7),as previously defined;

n is the integer one or three. n g In the above" metal coordination complex formulae, only one ligand (L) has to be optically active in order for the process of the reaction to be operable. g i If the optical activity ofthe ligand. resides in having an optically active group attached to the phosphorus or arsenic atom, there only has to be one such group, a nd the other two groups may be the same or inactive. In instance, only one "of the groups R R5, or R has'to be tical or inactive.

Catalysts which may be used include, but are not limited to, coordination complexes of the following formulae. In the formulae, an asterisk indicates asymmetry, and therefore optical activity. The asterisk denotes the asymmetric atom or dissymmetric group. As an example: R* indicates a dissymmetric group; A* indicates the phosphorus or arsenic is asymmetric. Absence of an asterisk indicates no optical activity. Y I

wherein M M X, A, R R and R are as previously defined. v

It is understood that in the above illustrated list of catalysts, the dissymmetric group can be R R or R and is not restricted to any one group. In addition, there may be a combination of moieties attached to the metal.

Substituents on the phosphorus and arsenic atoms include but are not limited to: methyl, ethyl, propyl, isopropyl, butyl and its isomers, pentyl and its isomers, hexyl and its isomers, heptyl and its isomers, octyl and its isomers, nonyl and its isomers, decyl and its isomers, undecyl and its isomers, dodecyl and its isomers, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acetonylphenyl, methylphenyl, ethylphenyl, propylphenyl, butylphenyl, dimethylphenyl, trimethylphenyl, diethylphenyl, benzyl, pyrrole, furan, pyridine, thiophene and piperidine. A list of phosphine and arsines which may be utilized includes but is not limited to:

methylethylphosphine, rnethylisopropylphosphine, ethylbutylphosphine, isopropylisobutylphosphine, methylphenylphosphine, ethylphenylphosphine, propylphenylphosphine, butylphenylphosphine, phenylbenzylphosphine, phenylpyrrolephosphine, ethylisopropylisobutylphosphine, methylphenyl-4-methylphenylphosphine, ethylphenyl-4-methylphenylphosphine, methylisopropylphenylphosphine, ethylphenyl-2,4,5-trimethylphenylphosphine, phenylbenzyl-4-dimethylaminophenylphosphine, phenylpyridylmethylphosphine, phenylcyclopentylethylphosphine, cyclohexylmethylisopropylphosphine and the arsenic derivatives of the'above.

Although only one optically active group or ligand is required in the coordination catalyst, it is preferred for ease 'ofpreparation that all three ligands are the same. It is also preferred that asymmetry reside on either the phosphorusor arsenic atom.

In a preferred embodiment of this process an olefin is selectively hydrogenated in the presence of an optically active coordinated rhodium or iridium complex accordingto the following equation:

wherein R R R and R are each independently selected from the group consisting of hydrogen, alkyl havbeing preferred; X is selected from the group consisting of hydrogen, fluorine, bromine, chlorine and iodine; L is the ligand AR R R wherein R R R is each independently selected from the group consisting of hydrogen, alkyl having a maximum of 12 carbon atoms, phenyl, benzyl, tolyl, xylyl, cycloalkyl having at least 3 and a maximum of 6 carbon atoms, pyrryl, thienyl, furyl, pyridyl, piperidyl, substituted alkyl said substituent being selected from the group consisting of carbonyl, amino and alkoxy having a maximum of two carbons, provided that the groups so selected give an optically active ligand as previously described.

The hydrogenation reaction is usually conducted in a solvent, such as benzene, ethanol, toluene, cyclohexane, and mixtures of these solvents. Almost any aromatic or saturated alkane or cycloalkane solvent, which is inactive to the hydrogenation conditions of this reaction, can be used. Since the hydrogenation reaction of this reaction is specific, solvents such as nitrobenzene can also be utilized. The preferred solvent system is a mixture of a polar and non-polar solvent.

The catalyst is added to the solvent either as a compound per se or as its components which then form the catalyst in situ. When the catalyst is added as its components it may be added prior to, or at the same time as the olefin and/or base. Components for the preparation of the catalyst in situ are the metal salt and the phosphine or arsine ligand. The catalyst is usually added in the range of about 0.005% to about 10%, based on the olefin content.

A tertiary base, such as triethylamine, may be added to the reaction mixture in order to combine with any HCl formed from the hydrogenation of the catalyst. When a base is used, it is added to the reaction mixture in the range of about 0.1% to about 2%, based on the olefin content.

After addition of the components to the solvent, hydrogen is added to the mixture until about 2 to about 5 times the mole quantity of olefin has been added. The pressure of the system will necessarily vary since it will be dependent upon size of hydrogenation apparatus, amount of components and amount of solvent. The initial gauge pressure, however, should be at least about 250 psi. Lower pressures, including atmospheric pressure, can be used, but said lower pressures may result in a slower rate of hydrogenation.

Reaction temperatures may be in the range of about 25 C. to about 100 C. Higher temperatures may be used but are normally not required and may lead to an increase of side reaction and loss in selectiveness.

It should be pointed out that although this invention is directed mainly to asymmetric hydrogenation, the catalyst can also be used in the selective hydrogenation of any olefin whether or not an optically active compound would result. The selectiveness is, therefore, not restricted to olefins which give optically active products.

Upon completion of the reaction which is determined by conventional means, the solvent is removed and the products and catalyst separated by conventional means.

Many natural products and medications exist in an optically active form. In these cases only one of the forms is ing at least one and a maximum of 6 carbon atoms, suby usually effective. Synthetic preparations of these compounds in the past has required an additional step of separating the products into its enantiomorphs. This process is expensive and time consuming. The processof the present invention permits the formation of optically active products thus eliminating much of the time consuming and expensive separation of enantiomorphs. Natural products such as the amino acids and flavoring agents can be asymmetrically prepared by this method. An example of this is given in Example 3 in which a-phenylacrylic acid is hydrogenated by the process of this invention to hydratropic acid, which is then reduced to the aldehyde or alcohol, both of which are fragrances, by conventional means. r

Amino acids can be prepared by reducing preferably a dibenzylamino compound by the process of this convention and then removing the dibenzyl groups by conventional means to yield the free amino group.

The following examples are illustrative only and the invention is not limited to them. In the following examples parts are by weight unless otherwise indicated.

EXAMPLE 1 The optically active phosphines and arsines are prepared according to the procedure of Mislow and Korpiun, J. Am. Chem. Soc., 89, 4784 (1967).

To a suitable vessel equipped with a stirring means, a temperature measuring means and a material addition means was charged 250 parts phenyldichlorophosphine, 240 parts pyridine and 495 parts hexane. The solution was cooled to about 510 C. and a mixture consisting of 96 parts methanol and 27 parts hexane was added, with stirring, over a period of about 1% hours. The resultant mixture was stirred for an additional 2 /2 hours as it warmed to about 25 C. This reaction was conducted in an inert nitrogen atmosphere.

Pyridine hydrochloride, formed during the reaction, was filtered and the filtrate concentrated. The yellow residue was distilled, collecting a colorless fraction boiling at 95.5-97 C./ 17 mm. (82% yield) (Harwood &

Grisely, J. Am. Chem. Soc., 82, 423 (1960)].

To 'a suitableivess el equipped with a stirring means, a temperature measuring means and a material addition means'was charged 11 parts dimethyl phenylphosphonite, 2.5 parts 'r'nethyl iodide and 9.parts toluene,"The resultant solution was slowly heated. The reaction 'is exothermic and the temperature increases to about 110?. C., the reaction mixture is maintained at a temperature of about 100- 120 C., and an additional 185 parts dimethylphenylphosphonite slowly added. Additional 1 amounts of methyl iodide, in: about 1 part increments, are occasionally added during the phosphonite addition. The reaction mixture was maintained at about 110 C. for an additional hour following the addition of-componen'ts; The reaction mixture wasthen distilled collecting the portion boiling at 148149 C./ 17 mm., (96% yield) [Harwo 'od 8: Grisley,

J. Am. Chem. Soc. 82, 423 1960)].

To a suitable vessel equipped with a stirring means, a condensing means, 'temperaturemeasuring means and a material iaddition means, was charged 187 parts methyl phenyl (methyl) phosphinate and 1600 parts carbon tetrachloride. ,;To this mixture was added 229 parts phosphorus pentachloride in three portions of 50 parts and one portion of 79 parts. A temperature rise was observed on the addition of the first three r; portions. The mixture was stirred atil about 60. C. for two hours and then the carbon tetrachloride and phosphorous oxychloride removed 'by distillation. The residue was distilled collecting the fraction boiling at 138-141" C./ 17 mm. (95% yield) [Metho- 6 den der Organishen Chemie (Houben-Weyl), vol. XII/I, p. 243].

To a suitable vessel equipped with a stirring means, a condensing means, a temperature measuring means, and a material addition means, was added 78 parts l-menthol and 72 parts diethyl ether. To the resultant solution was added 119 parts of triethylamine and the resultant mixture cooled to about 0 C. To this mixture was added, with stirring, 87 parts methylphenylphosphinic chloride over a period of about 1% hours while maintaining the temperature at about 0 C. The mixture was allowed to warm to about 25 C. and then heated at reflux for about 10 /2 hours.

The mixture was filtered to'remove the triethylamine hydrochloride and the filtrate concentrated. Pentane was added to the residue and the mixture filtered. The filtrate was then concentrated yielding a solid melting at 50- 65 C. I

Material recrystallized several times from hexane, then diethyl ether yielded a solid melting at 7882 C.

. Ph\0 G +omomomM Br i -omcmcn,

CH: CH:

To a suitable vessel equipped with a stirring means, temperature measuring means, material addition means and a condenser means, under an inert nitrogen. atmosphere, was'added 9.5 parts magnesium, 7 parts diethyl ether and a reaction initiating amount of iodine. A small amount of bromopropanewas added to initiate the reac tion and thena mixture consisting of 47 parts bromopropane and 123 parts diethyl ether was slowly added at a rate to maintain gentle refluxing of the reaction mixture. The reaction mixture was then cooled to about 25 C. and stirred for an additional two hours. 3

To this mixture was added a mixture consisting-of 12 parts menthyl.methylphenylphosphinate (prepared above) and 88 parts benzene. The diethyl ether was then removed and the resultant mixture heated at 78 C. for 64 hours. The reaction mixture was decomposed with a solution of ammonium chloride and then filtered. The precipitate was extracted with hot benzene and the extract combined with the filtrate. The organic layer was dried over sodium sulfate and the solvents removed yielding a yellow oil. The oil was chromatographed on a silica gel column with a hexane:benzene:diethyl ether (3:1:1) mixture to yield the product in a 61% yield.

To a suitable vessel, having an inert nitrogen atmosphere, equipped with a stirring means, temperature measuring means, and a material addition means, was charged 16 parts trichlorosilane and 88 parts benzene at a temperature of about C. To this mixture, at a temperature of about 4-6 C. was added a mixture consisting of 22 parts triethylamine and 44 parts benzene. The resultant mixture was then warmed to about 25 C. and a mixture consisting of 0.82 parts phenyl methylpropylphosphine oxide and 22 parts benzene was added. The mixture was then heated to about 60 C. over a two-hour period and then cooled to about 25 C.

The reaction mixture was decomposed with 75 parts of a 20% solution of sodium hydroxide followed by 35 parts of. water. The resultant mixture was allowed to stand for about hours and then the layers separated. The organic layer was then extracted with 5% hydrochloric acid, 15 twice with water and then dried over sodium sulfate. The solvent was then removed by distillation yielding the product in a 95% yield and having a 69% optical purity.

EXAMPLE 2 Preparation of rhodium III chloride tri- (methylpropylphenylphosphine) To a suitable vessel, having a nitrogen atmosphere, was charged 0.342 gms. (0.0013 moles) of rhodium III chloride trihydrate and 10 ml. methanol. To this was added dropwise over a 15 minute period, 0.76 gms. (0.0046 moles) of methylpropylphenylphosphine (prepared in Example 1) in 3 ml. of methanol. The mixture was allowed to stand for 1 hour during which time a yellow precipitate separated from the solution. The precipitate was removed by filtration yielding 0.21 gms. having a specific rotation [a] =69.3. (A.)

Concentration of the filtrate yielded an additional 0.13 gms. of product having a specific rotation [a] =56.4.

EXAMPLE 3 Asymmetric hydrogenation of a-phenylacrylic acid To a hydrogenation apparatus equipped with a pressure gauge, thermocouple and heating means, was charged 3 parts a-phenylacrylic acid, 0.021 parts catalyst (B) (prepared in Example 2), 10 parts benzene, 10 parts ethanol and 0.01 parts triethylamine.

The apparatus was purged and pressurized with hydro gen to a gauge reading of 350 p.s.i. (0.051 moles). The reaction vessel is then heated to 60 C. and shaken for 5 hours, during which time there was a decrease in pressure of 110 p.s.i. which is equivalent to the theoretical amount of hydrogen required for reaction.

The reaction mixture was dissolved in 10% sodium hydroxide and the resultant aqueous mixture extracted with ether or ether and benzene to remove the catalyst. The aqueous mixture was then acidified with concentrated hydrochloric acid and extracted with ether. The ether extract was dried over anhydrous sodium sulfate, concentrated and the residue distilled collecting the pdrtionboiling at 91-92 C./ 0.2 mm. This fraction in ethanol had a specific rotation [0;]; +12.2. This amounts to a 15% optical purity (22% based on the optical purity of the catalyst).

Repeating the reaction using catalyst (A) (prepared in Example 2) yielded a product having a 14% optical purity.

The reaction was repeated using a non-optically active rhodium III chloride-phosphine catalyst. This reaction yields a non-optically active product.

Reduction of the carboxyl group by known methods to either the aldehyde or alcohol gives rise to the known fragrances hydratropic aldehyde and hydratropic alcohol.

EXAMPLES 4-11 Other optically active compounds prepared byv the process of this invention are as follows:

Temperature, 0.,

initial pressure Product observed, Solvent Base (p.s.i.) M.P. or B.P. .a'mntorr, m (0.115): 00 400 13.1. 89 03 c. 25 mm. (CaHshN 25/350 M.P. 114115 C. H:EtOH, 1:1 00 350 M.P. 113-114" 0. H:Et0H, 1:1 (Cz H1):N 25/445 Ml. 113.5-114 C.

Product CHICHIQHCO (IJH2COOH o'moHoooH fln Olefin COOH cmoooH CODE 4 6...........,. Same as above.... Same as above..-..-..... R1101: (in

Example:

1 1 provided that at least one L group is optically active and n is one of the integers one or three.

2. A process according to Claim 1 in which R R R and R are each independently selected from the group consisting of hydrogen; alkyl having at least one and a maximum of six carbon atoms; substituted alkyl, said substituent being selected from the group consisting'of amino, hydroxy, nitro, carbonyl, carboxyl, carboxylic ester, said ester group having a maximum of 6 carbon atoms; phenyl; tolyl; xylyl; carboxyl; carboxylic ester, said ester group having a maximum of 6 carbon atoms; benzylamino; di-

catalyst 6. A process according to Claim Sin which R is methyl and R is propyl.

7. A process according to Claim in which R is carboxylic ester.

8. A process according to Claim 7 in which R isphcnyl.

9. A process according to Claim 7 in which R is dibenzylamino.

10. A process according to Claim 9 in which R is amino substituted alkyl.

11. A process according to Claim 10 in which said alkyl has a maximum of 6 carbon atoms and said amino is on the to carbon atom.

12. In a process for the homogeneous catalytic hydrogenation of an olefin provided that, upon hydrogenation,

(a) the olefin is capable of forming a racemic mixture,

and

(b) at least one of the carbon atoms united by the olefinic bond is capable of forming an asymmetric carbon, in the presence of a coordination metal complex hydrogenation catalyst comprising a metal selected from the group consisting of rhodium, iridium and ruthenium and aphosphine or arsine ligand, the improvement wherein at least one phosphine or arsine ligand is optically active, thereby resulting in an asymmetric synthesis in which one enantiomorph is obtained in a major amount.

13. A process according to Claim 12 wherein the metal is rhodium.

14. A process according to Claim 13 wherein the optically active ligand is a phosphine.

15. In a process for the homogeneous catalytic hydrogenation of an olefin, capable of existing as enantiomorphs upon hydrogenation of the olefinic bond, inthe presence of a coordination metal complex hydrogenation catalyst comprising a metal selected from the group consisting of rhodium, iridium and ruthenium and a phosphine or arsine ligand, the improvement wherein at least one phosphine or arsine ligand is optically active.

References Cited UNITED STATES PATENTS 3,270,087 8/1966 Heck 260-6839 3,324,018 6/1967 Fotis et a1. 204-162 3,454,644 7/1969 Dewhirst 260-5709 OTHER REFERENCES Horner et al.: T elrahedron Letters, No. 37, July 1968, pp. 4023-26.

Horner et al.: Angew'. Chem. Internal. Edit., vol. 7 (1968), No. 12, p. 942.

Morrison et al.: J.A.C.S., 93:5, Mar. 10, 1971,,pp. 1301-3.

Dang et al.: Chemical Communications, 1971, p. 481. Knowles et al.: Chem. Comm., pp. 1445-1446, 1968. Abley et al.: Chem. Comm., pp. 477-478 (1969).

LORRAINE A. WEINBERGER, Primary Examiner R. D. KELLY, Assistant Examiner I 260-429 R, 441, 491, 515 R, 537 R540, 568 R, 583 R, 583 R, 586 R, 607 R, 609 R, 632 R, 644, 645,668 R, 683.9

Patent Na. 3 ,sue ,uao mama November 19 197a Iriirentofls) wi lliam S Knowles and M. Jerome Sabackv It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 2 line 6% the formula which reads "(ix) M x A-R R R (AR R R should read "(1K) M x A- =R R R7 AR R R "4 Column 3 line 1 the formula which beads 10 M X (AR"= R R )(AR R R should read a 2 "(m M x AR* R5R' AR R R Column 5., line 2 and 3 'convention" should be corrected to read "invention".

Column 6 second formula in that column which reads in part a II H II H0 Ph C) i should read PK? I C I CH3 1. CH CH Columns 8 and 9 column 3 of the table under the heading of "Product, in Example 8 the CH attached to the benzene ring should be Signed and sealed this 18th day of February 1975.

(SEAL) Attesc:

. C3a MRSHALL DANN RUTH ('1 a MASON V Cissisner of Patents Attestlng Officer and Trademarks 

1. A PROCESS FOR THE ASYMMETRIC HYDROGENATION OF AN OLEFIN WHICH COMPRISES THE HYDROGENATION OF AN OLEFIN OF THE FORMULA 